Project Summary: Zika virus (ZIKV) is an emerging mosquito-transmitted flavivirus that has become a global public health threat. ZIKV infection has now been causally linked to cases of Guillain-Barre syndrome in adults and microcephaly, intrauterine growth restriction (IUGR), and spontaneous abortion in the setting of maternal infection during pregnancy. Given the recognition of this causal relationship, it is imperative to determine the mechanism(s) of maternal-fetal transmission. Insights into such mechanisms could improve our ability to reduce the burden of the effects of Zika virus infection during pregnancy. The goal of this collaborative and interactive project is to define how host defense responses can control or possibly contribute to ZIKV pathogenesis during and after pregnancy. The premise is based on the extensive newly published data showing that ZIKV infection of pregnant mice results in infection of the placenta, in utero transmission, and injury to the developing fetus. O ur central hypotheses are that maternal-fetal transmission occurs because ZIKV overcomes placental trophoblast host defenses (autophagy) (Aim 1), usurps TAM receptors to enter placental trophoblasts and endothelial cells (Aim 2); and this entire process is enhanced in flavivirus-immune individuals or animals who have sufficient levels of cross-reactive, non-neutralizing anti-ZIKV antibodies that promote ADE (Aim 3). Collectively, our efforts will be highly significant for understanding ZIKV pathogenesis. This work will provide a foundation for clinical studies that define the risks of maternal to child transmission of ZIKV, generate possible new therapeutic approaches, and determine the interaction between ZIKV and natural immunity to other flaviviruses.